Animal studies may or may not be relevant to human health. We should not dismiss a study simply because it was done on animals, but rather assess each study on its merits.
In this case, I’d mention a couple of thoughts. First, it is extremely difficult to get rats into ketosis. I corresponded briefly with Peter of the Hyperlipid blog, since he is a veterinarian, and it turns out that most mammals normally only enter ketosis during the late stages of starvation. (This dashed my hopes of extending my pet rats’ lives by putting them on a ketogenic diet.) Human beings are practically unique in being able to enter ketosis so readily.
This difference between rats and people may be relevant here, since the diet needed in order to get rats to make ketones is likely to be very different from a diet that does the same thing for human beings. So I am confused by the authors’ use of the term “ketogenic diet” in this context. It is possible that they are using the term simply to mean some kind of low-carbohydrate, high-fat diet, but I would like to know precisely what it was they fed the rats. Was this diet something that approximates what rats would eat in the wild? If not, that might be relevant. It would also be useful to know the duration of this experiment. (The diet and the duration may have been mentioned in the article; but I didn’t see this information as I skimmed.)
Second, it is entirely possible (though I’m not clear whether this study actually shows it) that too much β-hydroxybutyrate might cause heart damage in rats. On the other hand, Dr. Phinney cites, in a couple of his lectures available on YouTube, a study showing that β-hydroxybutyrate actually benefits the human heart, since it requires less oxygen to metabolise than fatty acids, a clear benefit for muscle served by occluded arteries. Β-hydroxybutyrate has also been shown to have many other benefits in the human body (and so have the other two ketone bodies, acetoacetate and acetone).
Third, I am puzzled by the statement in this article that claims that β-hydroxybutyrate causes damage to mitochondria, since β-hydroxybutyrate is actually produced by the mitochondria as they metabolise fatty acids. Ketone bodies are partial metabolites of fatty acids. When the liver is producing ketones for the rest of the body (ketogenesis), the process stops, and the ketones are distributed for use by cells that can use them. On the other hand, when muscles metabolise fatty acids, they produce ketone bodies midway through the process, which then continues until the ketones are reduced to carbon dioxide and water (much as wood first becomes charcoal as it burns and then is eventually reduced to carbon dioxide and ash).
We know that glucose metabolism can cause mitochondrial damage if the radical oxygen species (ROS) produced overwhelm the defenses against them, but I haven’t heard of similar damage from fatty-acid metabolism. So I suspect that this idea that β-hydroxybutyrate damages the heart may be a misinterpretation of the data, even in rats.
It also concerns me that the authors of the article speak of a ketogenic diet as a reduced-calorie diet. I think they are missing important nuances of how a ketogenic diet affects the human body. Given the difficulties of getting rats into ketosis, I would expect that assuming a ketogenic diet to be energy-deficient could affect how one interprets one’s observations.
Furthermore, I would point out that it can happen that the effects of a substance on cells in vitro may differ from the effects in vivo. The human body has evolved to a level of complexity that can handle most of what gets thrown at it. Cells in isolation can sometimes be affected differently, because they don’t have the full range of bodily processes to protect them. This is not to say that examining cells in vitro is without merit, only that care must be taken when analysing the results.
Lastly, I have to say that I find it highly unlikely that the diet on which the human race is known to have evolved could possibly be harmful. We know from anthropology and archaeology that human societies that eat almost entirely meat are much healthier than societies that adopt a largely plant-based diet.